Enzyme activity is known to be a vital factor in the lifecycle of viruses which infect mammals. Effective inhibitors of viral enzymes would, therefore, be useful therapeutic tools in the treatment of viral infections such as by HIV (Human Immunodeficiency Virus), and viral infection related diseases such as AIDS (Acquired Immune Deficiency Syndrome)aand ARC (AIDS Related Complex).
HIV, the causative agent of the AIDS, is a member of the lentivirus family of retroviruses (Gonda et al., 1985, "Sequence Homology and Morphological Similarity of HTLV III and Visna Virus, A Pathogenic Lentivirus", Science, 227:173; Sonigo et al., 1985, "Nucleotide Sequence of the Visna Lentivirus: Relationship to the AIDS Virus", Cell, 42:369). HIV, in common with other retroviruses, encodes a number of enzymes that are necessary for its life cycle (Weiss et al., 1982, The Molecular Biology of RNA Tumor Viruses, 2nd ed., Cold Spring Harbor Laboratory, New York; Ratner et al., 1985, "Complete Nucleotide Sequence of the AIDS Virus, HTLV III", Nature, 313:277). In the absence of such enzymes, viable viral infections do not occur (Weiss et al., supra).
The only currently used therapeutic for AIDS, AZT, is an inhibitor of the viral reverse transcriptase (Mitsuya et al., 1986, "Inhibition of the In Vitro Infectivity and Cytopathic Effects of HTLV III", Proc. Natl. Acad. Sci. U.S.A. 83:1911). Other known viral enzymes include an RNAse, an integrase and a protease, all of which are essential for the viral life cycle (Mitsuya et al., 1987, "Strategies for Antiviral Therapy in AIDS", Nature, 325:773).
The protease found in HIV (hereinafter "HIV protease") is responsible for cleavage of the gag and gag-pol polyproteins into mature peptides (Ratner et al. supra; Kramer et al., 1986, "HTLV III Gag Protein is Processed in Yeast cells by the Virus Pol Protease", Science, 231:1580; Farmerie et al., 1987, "Expression and Processing of the AIDS Virus Reverse Transcriptase in Escherichia coli", Science, 236:305). The amino acid sequence for the gag polyprotein is described in Ratner et al, 1985, Nature, 313:277.
From the known location at the 5' end of the pol gene and the inferred protease cleavage sites (Pearl et al., 1987, "Sequence Specificity of Retroviral Proteases," Nature, 328:482), the predicted size of the protease is 99 amino acids. HIV protease, as with other retroviral proteases, has a homology with cellular aspartyl proteases (Katch et al., 1987, "Inhibition of Retroviral Protease Activity by an Aspartyl Proteinase Inhibitor", Nature, 329:654 ).
Kohl et al., 1988, "Active Human Immuno-deficiency Virus Protease is Required for Viral Infectivity.", Proc. Natl. Acad. Sci. U.S.A., 85:4686, demonstrated that active HIV protease participation is required for HIV replication. The article by J. R. Huff, 1991, "HIV Protease: A Novel Chemotherapeutic Target for AIDS.", J. Med. Chem., 34:2305, is a state of the art review of currently documented HIV protease inhibitors.
The inventive compounds differ from those taught in the prior art of which the applicants are aware in that they represent peptidomimetics which contain a novel class of isosteres which are not presently known.